Defeating Drug-Resistant Cancers

Cell block: Up to 50 percent of patients with metastatic melanoma have a mutation in the BRAF protein (its structure is shown here) that renders the tumor susceptible to certain drugs. Scientists have now discovered how some tumor cells evolve resistance to those drugs.

Last August, oncologist Keith Flaherty and colleagues at Massachusetts General Hospital published a study that gave hope to patients with metastatic melanoma. But the good news was tempered by a serious caveat: in most patients, the drug eventually stopped working after anywhere from months to years.

This issue of drug resistance has plagued the new generation of so-called targeted cancer therapies, designed to block the effects of genetic mutations that drive the growth of cancer. In two new studies published last week in Nature, researchers from Dana Farber Cancer Institute in Boston and the University of California, Los Angeles, uncovered how some melanoma tumors fight back against these drugs. They say the insight will aid in the design of new drugs and drug combinations that will allow targeted therapies to work longer and maybe even overcome resistance altogether.

“If we can understand and anticipate the full spectrum of ways cancers can get around these drugs, we can come up with formulas for combinations of drugs that could have lasting control,” says Levi Garraway, an oncologist and scientist at Dana Farber.

In one study, Garraway, Flaherty, and collaborators analyzed the effects of 600 different protein kinases, which are types of enzymes, on melanoma tumor cells growing in a dish. They found that overactivity among nine of the protein kinases made the cells resistant the type of drug that was so promising in Flaherty’s melanoma study. One enzyme had never previously been implicated in cancer. The researchers confirmed the findings by analyzing tissue samples from melanoma patients who evolved resistance to the drug.

It’s not yet clear how common this particular mechanism of drug resistance is. But Flaherty says that, based on the findings, he is very optimistic about targeted therapies. “It’s not chaos that creates resistance, it’s the same rational cell and molecular biology that led to the development of these therapies in first place,” he says. “We don’t need to invoke some phenomenally complex network biology to figure this out.”

In a related paper in Nature,Roger Lo, a physician and scientist at UCLA’s Jonsson Comprehensive Cancer Center, found changes similar to those in Garraway’s study. Lo agrees that the results will help scientists figure out more effective drug combinations. He likened the approach to those used to eradicate stubborn viruses. “A cocktail would be designed to cut off any possible escape route,” he says. However, “it’s more daunting to cover all grounds for a cancer cell,” because such cells tend to be very “plastic,” or capable of change.

Lo also cautions that researchers have studied relatively few patients, so it’s not yet clear how broadly these findings will apply to larger numbers of patients. (One problem is that it’s hard to come by tissue samples—researchers need tissue from the same patient both before and after treatment.) The researchers found resistance mechanisms in about 40 percent of the drug-resistant patients they studied, and are now looking for explanations for the remaining 60 percent.